# Dual-Mechanism Allosteric Inhibitors of ERK Signaling

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2022 · $537,806

## Abstract

SUMMARY
There are currently no FDA-approved drugs available targeting the ERK pathway in which RAS
mutations drive ERK activity. The long-term goal is to help develop therapeutically useful ERK
inhibitors for the clinical treatment of malignancies. The overall objectives in this application are
to (i) characterize the chemical and allosteric mechanism and develop a novel class of covalent
ERK inhibitors, (ii) elucidate the molecular mechanism(s) by which they induce anti-proliferative
activity in combination with FDA-approved drugs vertically targeting the ERK pathway and (iii)
determine the in vivo anti-tumor efficacy of combination treatments using patient-derived organoid
and tumor models. The central hypothesis is that combination therapy using covalent, allosteric
inhibitors of ERK can be developed to possess suitable potency to induce apoptotic cell death
and promote tumor regression in patient-derived tumor models predictive of clinical efficacy. The
project's rationale is that developing a new chemical strategy to inhibit ERK and determination of
its preclinical therapeutic efficacy and associated mechanisms is likely to offer a robust scientific
framework for developing new cancer therapeutic approaches. Testing the central hypothesis
occurs by pursuing two specific aims: 1) The design and elucidation of the mechanism of ERK
recruitment site inhibitors and 2) investigating covalent ERK inhibitors in patient-derived CRC
Tumor Models. The first aim is to optimize a new class of covalent allosteric ERK inhibitors and
delineate allosteric binding and inhibition mechanisms to identify highly specific leads. The second
aim delineates ERK inhibition's mechanisms and consequences by leads in RAS- and RAF-
transformed patient-derived models and identifies agents that, combined with FDA-approved
drugs targeting the ERK pathway, induce tumor regression. In the applicant's opinion, the
research proposed in this application is innovative because it focuses on developing leads from
a new class of ERK inhibitor compounds that covalently target a site of protein binding on ERK.
These compounds will exhibit improved pharmacodynamics and block compensatory feedback
signals from ERK signaling and induce durable ERK inhibition to promote robust cytotoxic anti-
cancer effects. The proposed research is significant because it is expected to provide substantial
scientific justification for the continued development and future clinical trials of novel ERK inhibitor
therapies. Ultimately, such knowledge can offer new opportunities for the development of
innovative therapies to treat cancer.

## Key facts

- **NIH application ID:** 10446852
- **Project number:** 1R01CA262670-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Kevin N Dalby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $537,806
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446852

## Citation

> US National Institutes of Health, RePORTER application 10446852, Dual-Mechanism Allosteric Inhibitors of ERK Signaling (1R01CA262670-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10446852. Licensed CC0.

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